Drug delivery coating for use with a stent

ABSTRACT

A coated medical device and a method of providing a coating on an implantable medical device result in a medical device having a bio-absorbable coating. The coating includes a bio-absorbable carrier component. In addition to the bio-absorbable carrier component, a therapeutic agent component can also be provided. The coated medical device is implantable in a patient to effect controlled delivery of the coating, including the therapeutic agent, to the patient.

RELATED APPLICATIONS

This application is a continuation of, claims priority to, and thebenefit of U.S. patent application Ser. No. 11/236,908, now U.S. Pat.No. 8,263,102, filed Sep. 28, 2005, which claimed priority toProvisional Application No. 60/613,745, filed Sep. 28, 2004, for allsubject matter common to said applications. The complete disclosures ofall said applications are hereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to coatings suitable for application tomedical devices for delivery of one or more biologically active agents,and more particularly to a bio-absorbable coating able to providecontrolled short or long term release of biologically active componentsfrom the surface of an implanted medical device or prosthesis.

BACKGROUND OF THE INVENTION

Therapeutic agents may be delivered to a targeted location in a humanutilizing a number of different methods. For example, agents may bedelivered nasally, transdermally, intravenously, orally, or via otherconventional methods. Delivery may vary by release rate (i.e., quickrelease or slow release). Delivery may also vary as to how the drug isadministered. Specifically, a drug may be administered locally to atargeted area, or administered systemically.

With systemic administration, the therapeutic agent is administered inone of a number of different ways including orally, inhallationally, orintravenously to be systemically processed by the patient. However,there are drawbacks to systemic delivery of a therapeutic agent, one ofwhich is that high concentrations of the) therapeutic agent travels toall portions of the patient's body and can have undesired effects atareas not targeted for treatment by the therapeutic agent. Furthermore,large doses of the therapeutic agent only amplify the undesired effectsat non-target areas. As a result, the amount of therapeutic agent thatresults in application to a specific targeted location in a patient mayhave to be reduced when administered systemically to reducecomplications from toxicity resulting from a higher dosage of thetherapeutic agent.

An alternative to the systemic administration of a therapeutic agent isthe use of a targeted local therapeutic agent delivery approach. Withlocal delivery of a therapeutic agent, the therapeutic agent isadministered using a medical device or apparatus, directly by hand, orsprayed on the tissue, at a selected targeted tissue location of thepatient that requires treatment. The therapeutic agent emits, or isotherwise delivered, from the medical device apparatus, and/or carrier,and is applied to the targeted tissue location. The local delivery of atherapeutic agent enables a more concentrated and higher quantity oftherapeutic agent to be delivered directly at the targeted tissuelocation, without having broader systemic side effects. With localdelivery, the therapeutic agent that escapes the targeted tissuelocation dilutes as it travels to the remainder of the patient's body,substantially reducing or eliminating systemic side effects.

Local delivery is often carried out using a medical device as thedelivery vehicle. One example of a medical device that is used as adelivery vehicle is a stent. Boston Scientific Corporation sells theTaxus® stent, which contains a polymeric coating for deliveringPaclitaxel. Johnson & Johnson, Inc. sells the Cypher® stent whichincludes a polymeric coating for delivery of Sirolimus.

Targeted local therapeutic agent delivery using a medical device can befurther broken into two categories, namely, short term and long term.The short term delivery of a therapeutic agent occurs generally within amatter of seconds or minutes to a few days or weeks. The long termdelivery of a therapeutic agent occurs generally within several weeks toa number of months. Typically, to achieve the long term delivery of atherapeutic agent, the therapeutic agent must be combined with adelivery agent, or otherwise formed with a physical impediment as a partof the medical device, to slow the release of the therapeutic agent.

US Patent Publication No. 2003/0204168 is directed to the localadministration of drug combinations for the prevention and treatment ofvascular disease. The publication discusses using intraluminal medicaldevices having drugs, agents, and/or compounds affixed thereto to treatand prevent disease and minimize biological reactions to theintroduction of the medical device. The publication states that bothbio-absorbable and biostable compositions have been reported as coatingsfor stents. They have been polymeric coatings that either encapsulate apharmaceutical/therapeutic agent or drug, e.g. rapamycin, taxol etc., orbind such an agent to the surface, e.g. heparin-coated stents. Thesecoatings are applied to the stent in a number of ways, including, thoughnot limited to, dip, spray, or spin coating processes.

The publication goes on to state that although stents prevent at least aportion of the restenosis process, a combination of drugs, agents orcompounds which prevents smooth muscle cell proliferation, reducesinflammation and reduces thrombosis or prevents smooth muscle cellproliferation by multiple mechanisms, reduces inflammation and reducesthrombosis combined with a stent may provide the most efficacioustreatment for post-angioplasty restenosis. The systemic use of drugs,agents or compounds in combination with the local delivery of the sameor different drug/drug combinations may also provide a beneficialtreatment option.

The invention subsequently described in the '168 publication relates tothe provision of polymeric coatings comprising a polyfluoro copolymerand implantable medical devices, for example, stents coated with a filmof the polymeric coating in amounts effective to reduce thrombosisand/or restenosis when such stents are used in, for example, angioplastyprocedures. Blends of polyfluoro copolymers are also used to control therelease rate of different agents or to provide a desirable balance ofcoating properties, i.e. elasticity, toughness, etc., and drug deliverycharacteristics, for example, release profile. Polyfluoro copolymerswith different solubilities in solvents may be used to build updifferent polymer layers that may be used to deliver different drugs orto control the release profile of a drug.

The coatings and drugs, agents or compounds described are described asbeing useful in combination with any number of medical devices, and inparticular, with implantable medical devices such as stents andstent-grafts. Other devices such as vena cava filters and anastomosisdevices may be used with coatings having drugs, agents, or compoundstherein.

U.S. Pat. No. 6,358,556 is directed to a drug release stent coating. Thepatent describes processes for producing a relatively thin layer ofbiostable elastomeric material in which an amount of biologically activematerial is dispersed as a coating on the surfaces of a deployablestent. The coating is described as preferably being applied as amixture, solution, or suspension of polymeric material and finelydivided biologically active species dispersed in an organic vehicle or asolution or partial solution of such species in a solvent or vehicle forthe polymer and/or biologically active species. Essentially the activematerial is dispersed in a carrier material that may be a polymer, asolvent, or both.

U.S. Pat. No. 6,299,604 is directed to a coated implantable medicaldevice having a layer of bioactive material and a coated layer providingcontrolled release of the bioactive material. The patent discusses theidea that the degradation of an agent, a drug, or a bioactive material,applied to an implantable medical device may be avoided by covering theagent, drug, or bioactive material, with a porous layer of abiocompatible polymer that is applied without the use of solvents,catalysts, heat or other chemicals or techniques, which would otherwisebe likely to degrade or damage the agent, drug or material. Thosebiocompatible polymers may be applied preferably by vapor deposition orplasma deposition, and may polymerize and cure merely upon condensationfrom the vapor phase, or may be photolytically polymerizable and areexpected to be useful for this purpose. As such, this patent focuses onthe use of polymers to act as drug delivery agents in providing acontrolled release of a drug from an implanted medical device.

US Publication No. 2003/0004564 is directed to a drug delivery platform.The publication describes compositions and methods for a stent baseddrug delivery system. The stent comprises a matrix, where the matrix hasentrapped a pharmaceutical agent of interest. The matrix, for examplemicrospheres, etc. resides within a channel formed on one or both of theabluminal or adluminal surfaces of the stent, and allows for release,usually sustained release, of the entrapped agent. The stent and matrixis encased with a gel covalently bound to the stent surface andoptionally also covalently bound to the matrix, which prevents loss ofthe matrix during transport and implantation of the stent, and whichaffects the release of the biologically active agent, throughdegradation and diftbsion characteristics. The matrix is described as abiodegradable, bioerodible, or biocompatible non-biodegradable matrixcomprising a biologically active agent that is placed within thechannels of the stent surface. The matrix may be of any geometryincluding fibers, sheets, films, microspheres, circular discs, plaquesand the like. The gel is selected to be a polymeric compound that willfill the spaces between the matrix and the channel, that can becovalently bound to the stent surface and optionally covalently bound tothe matrix, and that provides a porous protective barrier between thematrix and the environment, for example during storage, implantation,flow conditions, etc. The gel may contribute to the control of drugrelease through its characteristics of degradation and diffusion.

U.S. Pat. No. 4,952,419 is directed to a method of making antimicrobialcoated implant devices. The reference discusses the desire to havebetter retention of coatings on the implant surface during mechanizedimplant packaging operations. The solution presented involves the use ofa silicone fluid in contact with the surface of the implant and anantimicrobial agent in contact with the silicone fluid. There is nodiscussion of any therapeutic benefit inherent in the silicone fluiditself, and there is no suggestion that other oils can be utilized tocontrol the delivery of the antimicrobial agent

The above-described references fail to teach or suggest the use ofbio-absorbable fats or oils in any form as the drug delivery platform.In each instance, the drug delivery platform includes the use of a formof polymeric material, or silicone material, with a solvent additive.The polymeric material serves as either a base upon which a drug coatingis applied, a substance mixed in with the drug to form the coating, or atop coating applied over a previously applied drug coating to controlthe release of the drug.

PCT application publication No. WO 00/62830 is directed to a system andmethod for coating medical devices using air suspension. The techniqueinvolves suspending a medical device in an air stream and introducing acoating material into the air stream such that the coating material isdispersed therein and coats the medical device. The publicationdiscusses applying the coating to a number of different medical devicesformed of a number of different materials. The publication furthersuggests that the coating materials can be comprised of therapeuticagents alone or in combination with solvents, and that the coating mayprovide for controlled release, which includes long-term or sustainedrelease. As stated in the publication, a list of coating materials otherthan therapeutic agents include polymeric materials, sugars, waxes, andfats applied alone or in combination with therapeutic agents, andmonomers that are cross-linked or polymerized. The publication goes onto discuss the use of a drug matrix formed of a polymer structure, whichcan be used to control the release rate of drugs combined with thepolymer.

Although the '830 publication attempts to discuss every possiblecombination of delivery coating in combination with every drug ortherapeutic agent that may have some utility in targeted deliveryapplications, there is no realization of the difficulty of using an oilfor the controlled release of a therapeutic agent in a long termapplication. A list of potential delivery vehicles identifies waxes andfats, however there is no indication that such vehicles can be utilizedfor anything other than a short term drug delivery. A later discussionof controlled long term release of a drug mentions only the use ofpolymers to control the release.

U.S. Pat. No. 6,117,911 is directed to the use of compounds anddifferent therapies for the prevention of vascular and non-vascularpathologies. The '911 patent discusses the possibility of using manydifferent types of delivery methods for a therapeutic agent or agents toprevent various vascular and non-vascular pathologies. One such approachis described as providing a method of preventing or treating a mammalhaving, or at risk of developing, atherosclerosis, includingadministering an amount of a combination of aspirin or an aspirinate andat least one omega-3 fatty acid, wherein said amount of omega-3 fattyacid is effective to maintain or increase the level of TGF-beta so as toprovide a synergistic effect with a therapeutic compound to inhibit orreduce vessel lumen diameter dimension. As such, the patent discussessome of the therapeutic benefits of primarily systemic administration ofomega-3 fatty acids to affect TGF-beta levels when a therapeutic agentis combined with aspirin or aspirinate. That is, the dose orconcentration of omega-3-fatty acid required to increase the level ofTGF-beta is significantly greater, requiring long term systemicdelivery.

PCT Application Publication No. WO 03/028622 is directed to a method ofdelivering drugs to a tissue using drug coated medical devices. The drugcoated medical device is brought into contact with the target tissue orcirculation and the drugs are quickly released onto the area surroundingthe device in a short period of time after contact is made. The releaseof the drug may occur over a period of 30 seconds, I minute or 3minutes. In one embodiment described in the publication, the carrier ofthe drug is a liposome. Other particles described as potential drugcarriers include lipids, sugars, carbohydrates, proteins, and the like.The publication describes these carriers as having propertiesappropriate for a quick short term release of a drug combined with thecarriers.

PCT application publication No. WO 02/100455 is directed to ozonatedmedical devices and methods of using ozone to prevent complications fromindwelling medical devices. The application discusses having the ozonein gel or liquid form to coat the medical device. The ozone can bedissolved in olive oil, or other types of oil, to form a gel containingozone bubbles, and the gel applied to the medical device as a coating.The application later asserts a preference for the gel or other coatingformulation to be composed so that the ozone is released over time.However, there is no indication in the application as to how a slowcontrolled release of ozone can be affected. There is no enablement to along term controlled release of ozone from the olive oil gel, however,there is mention of use of biocompatible polymers to form the coatingthat holds and releases the ozone. Other drugs are also suggested forcombination with the ozone for delivery to a targeted location. Theapplication later describes different application methods for thecoating, including casting, spraying, painting, dipping, sponging,atomizing, smearing, impregnating, and spreading.

U.S. Pat. No. 5,509,899 is directed to a medical device having alubricious coating. In the background section of this patent, it statesthat catheters have been rendered lubricious by coating them with alayer of silicone, glycerin, or olive oil in the past. It further statesthat such coatings are not necessarily satisfactory in all cases becausethey tend to run off and lose the initial lubricity rather rapidly andthey can also lack abrasion resistance. Hydrophilic coatings have alsobeen disclosed such as polyvinyl pyrrolidone with polyurethaneinterpolymers or hydrophilic polymer blends of thermoplasticpolyurethane and polyvinyl pyrrolidone. Accordingly, the invention inthe '899 patent is described as providing a biocompatible surface for adevice which can impede blocking or sticking of two polymer surfaceswhen the surfaces are placed in tight intimate contact with each othersuch as is the case when the balloon is wrapped for storage or when asurface of one device will contact a surface of another device. Thedescription goes on to describe numerous polymeric substances.

European Patent Application No. EP 1 273 314 is directed to a stenthaving a biologically and physiologically active substance loaded ontothe stent in a stable manner. The biologically and physiologicallyactive substance is gradually released over a prolonged period of timewith no rapid short term release. In order to achieve the long termcontrolled release, the application describes placing a layer of thebiologically and physiologically active substance on the surface of thestent, and placing a polymer layer on top of the biologically andphysiologically active substance layer. The polymer layer acts to slowthe release of the biologically and physiologically active substance.There is no discussion of an alternative to the polymer substanceforming the polymer layer for controlling the release of thebiologically and physiologically active substance. There are instancesdiscussed when the biologically and physiologically active substance hasinsufficient adhesion characteristics to adhere to the stent. In suchinstances, the application describes using an additional substance mixedwith the biologically and physiologically active substance to increaseits adhesion properties. In the case of a fat soluble substance, therecommendation is the use of a low molecular weight fatty acid having amolecular weight of up to 1000, such as fish oil, vegetable oil, or afat-soluble vitamin such as vitamin A or vitamin E. The applicationalways requires use of the additional polymer coating to create the longterm controlled release of the biologically and physiologically activesubstance.

A paper entitled “Evaluation of the Biocompatibility and Drug DeliveryCapabilities of Biological Oil Based Stent Coatings”, by Shengqiao Li ofthe Katholieke Universiteit Leuven, discusses the use of biological oilsas a coating for delivering drugs after being applied to stents. Threedifferent coatings were discussed, a glue coating (cod liver oil mixedwith 100% ethanol at a 1:1 ratio), a vitamin E coating (97% vitamin Eoil solution mixed with 100% ethanol at a 1:1 ratio), and a glue+vitaminE coating (cod liver oil and 97% vitamin E oil solution mixed with 100%ethanol at a 1:1 ratio). Bare stents and polymer coated stents, alongwith stents having each of the above coatings, were implanted into testsubjects, and analyzed over a four week period. At the end of theperiod, it was observed that the bare stents and polymer coated stentsresulted in some minor inflammation of the tissue. The main finding ofthe study was that the glue coatings have a good biocompatibility withcoronary arteries, and that the glue coating does not affect the degreeof inflammation, thrombosis, and neointimal proliferation afterendovascular stenting compared with the conventional stenting approach.A further hypothesis asserted was that the oil coating providedlubrication to the stent, thus decreasing the injury to the vascularwall.

The study went on to analyze the drug loading capacity of biological oilbased stent coatings. Balloon mounted bare stents were dip-coated in abiological oil solution with the maximal solublizable amount ofdifferent drugs (a separate drug for each trial), and compared withpolymer coated, drug loaded, stents. According to the release ratecurves, there was a clear indication that drug release was fast in thefirst 24 hours with more than 20% of the drug released, for the oilbased coatings. The release rate after the first 24 hours was muchslower, and continued for a period up to about six weeks.

Another aspect of the study looked at the efficacy of drug loadedbiological stents to decrease inflammation and neointimal hyperplasia ina porcine coronary stent model. In this part of the study, glue ormodified glue (biological oil) coated stainless steel stents were loadedwith different drugs. The result was that the characteristics of theparticular drug loaded onto the stent were the major factor to thereduction of restenosis, and the biological oil did not have a majorimpact on either causing or reducing inflammation.

A further comment indicated that in the studies comparison was madebetween biological oil based drug loaded stents and bare stents to finddifferences in inflammation, injury, and hyperplasia. Inflammation,injury, and neointimal hyperplasia resulted in in-stent area stenosis.Any anti-inflammation observed was the result of the particular drugloaded on the stent, regardless of biological oil, or polymer, coating.

PCT Application Publication No. WO 03/039612 is directed to anintraluminal device with a coating containing a therapeutic agent. Thepublication describes coating an intraluminal device with a therapeuticagent comprised of a matrix that sticks to the intraluminal device. Thematrix is formed of a bio-compatible oil or fat, and can further includealfa-tocopherol. The publication further indicates that an oil or fatadheres sufficiently strongly to the intraluminal device so that most ofthe coating remains on the intraluminal device when it is inserted in abody lumen. The publication further states that the oil or fat slows therelease of the therapeutic agent, and also acts as an anti-inflammatoryand a lubricant. The publication goes on to indicate that the oil or fatcan be chemically modified, such as by the process of hydrogenation, toincrease their melting point. Alternatively, synthetic oils could bemanufactured as well. The oil or fat is further noted to contain fattyacids.

The '612 publication provides additional detail concerning the preferredoil or fat. It states that a lower melting point is preferable, and amelting point of 0° C. related to the oils utilized in experiments. Thelower melting point provides a fat in the form of an oil rather than awax or solid. It is further stated that oils at room temperature can behydrogenated to provide a more stable coating and an increased meltingpoint, or the oils can be mixed with a solvent such as ethanol.Preferences were discussed for the use of oils rather than waxes orsolids, and the operations performed on the fat or oil as described canbe detrimental to the therapeutic characteristics of some oils,especially polyunsaturated oils containing omega-3 fatty acids.

US Publication No. 2003/0083740 similarly discusses the use of certainoils as a matrix for delivery of drugs. More specifically, thispublication is directed to a method for forming liquid coatings formedical devices such as stents and angioplasty balloons. The liquidcoatings can be made from biodegradable materials in liquid, low meltingsolid, or wax forms, which preferably degrade in the body withoutproducing potentially harmful fragments. These fragments occur withharder coatings that fracture and break off after implantation. Theliquid coatings may also contain biologically active components, such asdrugs, which are released from the coatings through diffusion from thecoatings and the degradation of the coatings.

Some of this second group of references do refer to the use of oils as adrug delivery platform. However, there is no realization of thedifficulty of using an oil for the controlled release of a therapeuticagent in a long term application. There is further no indication thatthe coatings described in the above references are bio-absorbable, whilealso providing a controlled release of biologically active components,such as drugs. For controlled release of a drug, the above referencesrequire use of a polymer based coating either containing the drug orapplied over the drug on the medical device.

What is desired is a bio-absorbable delivery agent havingnon-inflammatory characteristics that is able to be prepared incombination with at least one therapeutic agent for the delivery of thattherapeutic agent to body tissue in a long term controlled releasemanner.

SUMMARY OF THE INVENTION

There is a need for a bio-absorbable coating for application to animplantable medical device for therapeutic purposes. The presentinvention is directed toward further solutions to address this need.

In accordance with one embodiment of the present invention, a coatedmedical device includes a coating having a bio-absorbable carriercomponent, the bio-absorbable carrier component being at least partiallyformed of a cellular uptake inhibitor and a cellular uptake enhancer.The coating further includes a solubilized or dispersed therapeuticagent. The coated medical device is implantable in a patient to effectcontrolled delivery of the therapeutic agent to the patient. Thecontrolled delivery is at least partially characterized by total andrelative amounts of the cellular uptake inhibitor and cellular uptakeenhancer in the bio-absorbable carrier component.

In accordance with aspects of the present invention, the bio-absorbablecarrier component contains lipids. The bio-absorbable carrier componentcan be a naturally occurring oil, such as fish oil. The bio-absorbablecarrier component can be modified from its naturally occurring state toa state of increased viscosity in the form of a cross-linked gel. Thebio-absorbable carrier component can contain omega-3 fatty acids.

It should be noted that as utilized herein, the term fish oil fatty acidincludes but is not limited to omega-3 fatty acid, fish oil fatty acid,free fatty acid, triglycerides, or a combination thereof. The fish oilfatty acid includes one or more of arachidic acid, gadoleic acid,arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid orderivatives, analogs and pharmaceutically acceptable salts thereof.Furthermore, as utilized herein, the term free fatty acid includes butis not limited to one or more of butyric acid, caproic acid, caprylicacid, capric acid, lauric acid, myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucicacid, lignoceric acid, analogs and pharmaceutically acceptable saltsthereof.

It should be noted that the term cross-linked gel, as utilized hereinwith reference to the present invention, refers to a gel that isnon-polymeric and is derived from an oil composition comprisingmolecules covalently cross-linked into a three-dimensional network byone or more of ester, ether, peroxide, and carbon-carbon bonds in asubstantially random configuration. In various preferred embodiments,the oil composition comprises a fatty acid molecule, a glyceride, andcombinations thereof.

In accordance with further aspects of the present invention thetherapeutic agent component mixes with the bio-absorbable carriercomponent. The therapeutic agent component can include an agent selectedfrom the group consisting of antioxidants, anti-inflammatory agents,anti-coagulant agents, drugs to alter lipid metabolism,anti-proliferatives, anti-neoplastics, tissue growth stimulants,functional protein/factor delivery agents, anti-infective agents,imaging agents, anesthetic agents, chemotherapeutic agents, tissueabsorption enhancers, anti-adhesion agents, germicides, antiseptics,proteoglycans, GAG's, gene delivery (polynucleotides), antifibrotics,analgesics, prodrugs, polysaccharides (e.g., heparin), anti-migratoryagents, pro-healing agents, and ECM/protein production inhibitors. Thetherapeutic agent component can alternatively take the form of an agentselected from the group consisting of cerivastatin, cilostazol,fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, andsimvastatin. The coating can be bio-absorbable, inhibit restenosis,and/or be non-polymeric.

In accordance with further aspects of the present invention, the coatingcan optionally include a solvent. The solvent can be Ethanol,N-Methyl-2-Pyrrolidone (NMP), or some other solvent compatible with thecoating, therapeutic agent, and intended use. The coating can furtherinclude a compatibilizer, such as vitamin E or its derivatives, whichalso acts as a stabilizer and/or preservative, therapeutic agent,antioxidant, thickener, or tactifyer.

It should be noted that as utilized herein to describe the presentinvention, the term vitamin E and the term alpha-tocopherol, areintended to refer to the same or substantially similar substance, suchthat they are interchangeable and the use of one includes an implicitreference to both. Further included in association with the term vitaminE are such variations including but not limited to one or more ofalpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol,alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol,gamma-tocotrienol, alpha-tocopherol acetate, beta-tocopherol acetate,gamma-tocopherol acetate, delta-tocopherol acetate, alpha-tocotrienolacetate, beta-tocotrienol acetate, delta-tocotrienol acetate,gamma-tocotrienol acetate, alpha-tocopherol succinate, beta-tocopherolsuccinate, gamma-tocopherol succinate, delta-tocopherol succinate,alpha-tocotrienol succinate, beta-tocotrienol succinate,delta-tocotrienol succinate, gamma-tocotrienol succinate, mixedtocopherols, vitamin E TPGS, derivatives, analogs and pharmaceuticallyacceptable salts thereof. It should also be noted that otherantioxidants may be used as a substitute to fulfill the functions ofVitamin E in this coating.

In accordance with further aspects of the present invention, the medicaldevice can be a stent. The stent can be formed of a metal. The stent canfurther be formed of a substance selected from the group consisting ofstainless steel, Nitinol alloy, nickel alloy, titanium alloy,cobalt-chromium alloy, ceramics, plastics, and polymers.

In accordance with further aspects of the present invention, the surfaceof the medical device can be provided with a surface preparation priorto the application of the coating comprising the bio-absorbable carriercomponent. The pre-treatment, or preparation of the surface, improvescoating conformability and consistency and enhances the adhesion of thecoating comprising the bio-absorbable carrier component. Thepre-treatment can be bio-absorbable, and can contain lipids. Thepre-treatment can be a naturally occurring oil, such as fish oil, andcan be modified from its naturally occurring state to state of increasedviscosity in the form of a cross-linked gel. The pre-treatment cancontain omega-3 fatty acids.

In accordance with one embodiment of the present invention, a method ofmaking a coated medical device includes providing the medical device. Acoating is applied, the coating including a bio-absorbable carriercomponent. The coated medical device is implantable in a patient toeffect controlled delivery of the coating to the patient.

In accordance with another embodiment of the present invention, a methodof making a coated medical device includes providing the medical device.A coating is applied having a bio-absorbable carrier component, thebio-absorbable carrier component being at least partially formed of acellular uptake inhibitor and a cellular uptake enhancer. The coatingfurther includes a solubilized or dispersed therapeutic agent. Thecoated medical device is implantable in a patient to effect controlleddelivery of the therapeutic agent to the patient. The controlleddelivery is at least partially characterized by total and relativeamounts of the cellular uptake inhibitor and cellular uptake enhancer inthe bio-absorbable carrier component.

In accordance with aspects of the present invention, the bio-absorbablecarrier component can contain lipids, and can be naturally occurringoil, such as fish oil.

In accordance with aspects of the present invention, the method canfurther include modifying the bio-absorbable carrier component from itsnaturally occurring state to a state of increased viscosity in the formof a cross-linked gel. The bio-absorbable carrier component can containomega-3 fatty acids.

In accordance with further aspects of the present invention, the methodcan further include providing the coating with a therapeutic agentcomponent. The therapeutic agent component mixes with the bio-absorbablecarrier component. The coating can be bio-absorbable, can inhibitrestenosis, and/or can be non-polymeric.

In accordance with further aspects of the present invention, the methodcan further include providing a solvent mixed with the bio-absorbablecarrier to form the coating. The solvent can be Ethanol, NMP, or othersolvent compatible with the coating and the therapeutic component. Themethod can further include providing a compatibilizer, such as vitaminE, which also acts as a stabilizer and preservative during formation ofthe coating. Alternatively, the solvent can be removed with vacuum orheat.

The medical device coating using the method can be a stent. The stentcan be formed of a metal, or other substance such as stainless steel,Nitinol alloy, nickel alloy, titanium alloy, cobalt-chromium alloy,ceramics, plastics, and polymers.

In accordance with further aspects of the present invention, the methodcan further include providing a surface preparation or pre-treatment onthe surface of the medical device prior to application of the coatingcomprising the bio-absorbable carrier component, wherein thepre-treatment improves the coating consistency and conformability andenhances the adhesion of the coating comprising the bio-absorbablecarrier component. The pre-treatment can be bio-absorbable, containlipids, and/or take the form of a naturally occurring oil, such as fishoil. The pre-treatment can be modified from its natural state to a stateof increased viscosity in the form of a cross-linked gel. Thepre-treatment can likewise contain omega-3 fatty acids.

In accordance with another embodiment of the present invention, a methodof making a coated medical device includes providing the medical device.A coating is applied to the medical device having a bio-absorbablecarrier component and a therapeutic agent component. The coated medicaldevice is implantable in a patient to effect controlled delivery of thecoating to the patient.

In accordance with one aspect of the present invention, the method canfurther include preparing the coating prior to application to themedical device. Preparing the coating can include mixing vitamin E andthe bio-absorbable carrier component to form a first mixture. Solventand the therapeutic agent component are mixed to form a second mixture.The first mixture and the second mixture are then mixed to form acoating substance. The first mixture and the second mixture can becreated independently and interchangeably first, second, orsubstantially simultaneously.

In accordance with further aspects of the present invention, the step ofapplying the coating can include at least one of dipping the medicaldevice in the coating substance, spraying the coating substance on themedical device, brushing the coating substance on the medical device,swabbing the coating substance on the medical device, painting thecoating substance on the medical device, wiping the coating substance onthe medical device, printing the coating substance on the medicaldevice, and electrostatically applying the coating substance to themedical device, with or without an applicator.

The method can further include curing the coating on the medical device.Curing can involve applying at least one of heat, UV light, chemicalcross-linker, or reactive gas to cure the coating. Curing with respectto the present invention generally refers to thickening, hardening, ordrying of a material brought about by heat, UV, or chemical means.

The method can further include sterilizing the coating and the medicaldevice. Sterilization can involve use of at least one of ethylene oxide,gamma radiation, e-beam, steam, gas plasma, and vaporized hydrogenperoxide (VHP).

The method can further include providing a surface preparation orpre-treatment on the surface of the medical device prior to applicationof the coating comprising the bio-absorbable carrier component, whereinthe pre-treatment improves the coating consistency and conformabilityand enhances the adhesion of the coating comprising the bio-absorbablecarrier component. The pre-treatment can be bio-absorbable, and/or canbe a naturally occurring oil, such as fish oil.

BRIEF DESCRIPTION OF THE DRAWINGS

The aforementioned features and advantages, and other features andaspects of the present invention, will become better understood withregard to the following description and accompanying drawings, wherein:

FIG. 1 is a diagrammatic illustration of a medical device, according toone embodiment of the present invention;

FIG. 2 is a cross-sectional view of the medical device in accordancewith one aspect of the present invention;

FIG. 3 is a cross-sectional view of the medical device in accordancewith another aspect of the present invention;

FIG. 4 is a flow chart illustrating a method of making the coatedmedical device of the present invention, in accordance with oneembodiment of the present invention;

FIG. 5 is a flow chart illustrating a variation of the method of FIG. 4,in accordance with one embodiment of the present invention;

FIG. 6 is a flow chart illustrating another variation of the method ofFIG. 4, in accordance with one embodiment of the present invention;

FIG. 7 is a flow chart illustrating another variation of the method ofFIG. 4, in accordance with one embodiment of the present invention;

FIG. 8 is a diagrammatic illustration of a coated medical device inaccordance with one embodiment of the present invention;

FIG. 9 is a graph depicting the amount of methylprednisone released overtime in water from a coated stent prepared in accordance with Example17;

FIG. 10 is a graph depicting the amount of methylprednisone releasedover time in water from a coated stent prepared in accordance withExample 18;

FIG. 11 is a graph depicting the cumulative amount of cilostazolreleased over time in water from three individual coated stents preparedin accordance with Examples 15, 16 and 19;

FIG. 12 is a graph depicting the percentage of paclitaxel released overtime in a 35% solution of acetonitrile/water from a coated stentprepared in accordance with Example 21; and

FIG. 13 is a graph comparing the amount of rapamycin released over timein a phosphate buffered saline (PBS) solution from high dose, low doseand high dose extended-release coated stents prepared in accordance withthe present invention relative to a known stent.

DETAILED DESCRIPTION

An illustrative embodiment of the present invention relates to theprovision of a coating on an implantable medical device. The coatingincludes a bio-absorbable carrier component. In addition to thebio-absorbable carrier component, a therapeutic agent component can alsobe provided. The coated medical device is implantable in a patient toeffect controlled delivery of the coating to the patient.

As utilized herein, the term “bio-absorbable” generally refers to havingthe property or characteristic of being able to penetrate the tissue ofa patient's body. In certain embodiments of the present inventionbio-absorption occurs through a lipophilic mechanism. The bio-absorbablesubstance is soluble in the phospholipid bi-layer of cells of bodytissue, and therefore impacts how the bio-absorbable substancepenetrates into the cells.

It should be noted that a bio-absorbable substance is different from abiodegradable substance. Biodegradable is generally defined as capableof being decomposed by biological agents, or capable of being brokendown by microorganisms or biological processes, in a manner that doesnot result in cellular uptake of the biodegradable substance.Biodegradation thus relates to the breaking down and distributing of asubstance through the patient's body, verses the penetration of thecells of the patient's body tissue. Biodegradable substances can causeinflammatory response due to either the parent substance or those formedduring breakdown, and they may or may not be absorbed by tissues.

The phrase “controlled release” generally refers to the release of abiologically active agent in a predictable manner over the time periodof weeks or months, as desired and predetermined upon formation of thebiologically active agent on the medical device from which it is beingreleased. Controlled release includes the provision of an initial burstof release upon implantation, followed by the predictable release overthe aforementioned time period.

With regard to the aforementioned oils, it is generally known that thegreater the degree of unsaturation in the fatty acids the lower themelting point of a fat, and the longer the hydrocarbon chain the higherthe melting point of the fat. A polyunsaturated fat, thus, has a lowermelting point, and a saturated fat has a higher melting point. Thosefats having a lower melting point are more often oils at roomtemperature. Those fats having a higher melting point are more oftenwaxes or solids at room temperature. Therefore, a fat having thephysical state of a liquid at room temperature is an oil. In general,polyunsaturated fats are liquid oils at room temperature, and saturatedfats are waxes or solids at room temperature.

Polyunsaturated fats are one of four basic types of fat derived by thebody from food. The other fats include saturated fat, as well asmonounsaturated fat and cholesterol. Polyunsaturated fats can be furthercomposed of omega-3 fatty acids and omega-6 fatty acids. Under theconvention of naming the unsaturated fatty acid according to theposition of its first double bond of carbons, those fatty acids havingtheir first double bond at the third carbon atom from the methyl end ofthe molecule are referred to as omega-3 fatty acids. Likewise, a firstdouble bond at the sixth carbon atom is called an omega-6 fatty acid.There can be both monounsaturated and polyunsaturated omega fatty acids.

Omega-3 and omega-6 fatty acids are also known as essential fatty acidsbecause they are important for maintaining good health, despite the factthat the human body cannot make them on its own. As such, omega-3 andomega-6 fatty acids must be obtained from external sources, such asfood. Omega-3 fatty acids can be further characterized as containingeicosapentaenoic acid (EPA), docosahexanoic acid (DHA), andalpha-linolenic acid (ALA). Both EPA and DHA are known to haveanti-inflammatory effects and wound healing effects within the humanbody.

Oil that is hydrogenated becomes a waxy solid. Attempts have been madeto convert the polyunsaturated oils into a wax or solid to allow the oilto adhere to a device for a longer period of time. One such approach isknown as hydrogenation, which is a chemical reaction that adds hydrogenatoms to an unsaturated fat (oil) thus saturating it and making it solidat room temperature. This reaction requires a catalyst, such as a heavymetal, and high pressure. The resultant material forms anon-cross-linked semi-solid. Hydrogenation can reduce or eliminateomega-3 fatty acids, and any therapeutic effects (both anti-inflammatoryand wound healing) they offer.

In addition, some curing methods have been indicated to have detrimentaleffects on the therapeutic agent combined with the omega-3 fatty acid,making them partially or completely ineffective. As such, oils, and morespecifically oils containing omega-3 fatty acids, have been utilized asa delivery agent for the short term uncontrolled release of atherapeutic agent, so that minimal or no curing is required. However,there are no known uses of oils containing omega-3 fatty acids forcombination with a therapeutic agent in a controlled release applicationthat makes use of the therapeutic benefits of the omega-3 fatty acids.Further, some heating of the omega-3 fatty acids to cure the oil canlessen the total therapeutic effectiveness of the omega-3 fatty acids,but not eliminate the therapeutic effectiveness. One characteristic thatcan remain after certain curing by heating methods is thenon-inflammatory response of the tissue when exposed to the curedmaterial. As such, an oil containing omega-3 fatty acids can be heatedfor curing purposes, and still maintain some or even a substantialportion of the therapeutic effectiveness of the omega-3 fatty acids. Inaddition, although the therapeutic agent combined with the omega-3 fattyacid and cured with the omega-3 fatty acid can be rendered partiallyineffective, the portion remaining of the therapeutic agent can, inaccordance with the present invention, maintain pharmacological activityand in some cases be more effective than an equivalent quantity of agentdelivered with other coating delivery agents. Thus, if for example, 80%of a therapeutic agent is rendered ineffective during curing, theremaining 20% of therapeutic agent, combined with and delivered by thecoating can be efficacious in treating a medical disorder, and in somecases have a relatively greater therapeutic effect than the samequantity of agent delivered with a polymeric or other type of coating.

For long term controlled release applications, polymers, as previouslymentioned, have been utilized in combination with a therapeutic agent.Such a combination provides a platform for the controlled long termrelease of the therapeutic agent from a medical device. However,polymers have been determined to themselves cause inflammation in bodytissue. Therefore, the polymers often must include at least onetherapeutic agent that has an anti-inflammatory effect to counter theinflammation caused by the polymer delivery agent. In addition, patientsthat received a polymer-based implant must also follow a course of longterm systemic anti-platelet therapy, on a permanent basis, to offset thethrombogenic properties of the non-absorbable polymer. A significantpercentage of patients that receive such implants are required toundergo additional medical procedures, such as surgeries (whetherrelated follow-up surgery or non-related surgery) and are required tostop their anti-platelet therapy. This can lead to a thrombotic event,such as stroke, which can lead to death. Use of the inventive coatingdescribed herein can negate the necessity of anti-platelet therapy, andthe corresponding related risks described, because there is nothrombogenic polymer reaction to the coating.

FIGS. 1 through 13, wherein like parts are designated by like referencenumerals throughout, illustrate an example embodiment of a coatedmedical device according to the present invention. Although the presentinvention will be described with reference to the example embodimentsillustrated in the figures, it should be understood that manyalternative forms can embody the present invention. One of ordinaryskill in the art will additionally appreciate different ways to alterthe parameters of the embodiments disclosed, such as the size, shape, ortype of elements or materials, in a manner still in keeping with thespirit and scope of the present invention.

FIG. 1 illustrates a stent 10 in accordance with one embodiment of thepresent invention. The stent 10 is representative of a medical devicethat is suitable for having a coating applied thereon to effect atherapeutic result. The stent 10 is formed of a series of interconnectedstruts 12 having gaps 14 formed therebetween. The stent 10 is generallycylindrically shaped. Accordingly, the stent 10 maintains an interiorsurface 16 and an exterior surface 18.

One of ordinary skill in the art will appreciate that the illustrativestent 10 is merely exemplary of a number of different types of stentsavailable in the industry. For example, the strut 12 structure can varysubstantially. The material of the stent can also vary from a metal,such as stainless steel, Nitinol, nickel, and titanium alloys, to cobaltchromium alloy, ceramic, plastic, and polymer type materials. One ofordinary skill in the, art will further appreciate that the presentinvention is not limited to use on stents. Instead, the presentinvention has application on a wide variety of medical devices. Forpurposes of clarity, the following description will refer to a stent asthe exemplar medical device. The terms medical device and stent areinterchangeable with regard to the applicability of the presentinvention. Accordingly, reference to one or another of the stent, or themedical device, is not intended to unduly limit the invention to thespecific embodiment described.

FIG. 2 illustrates one example embodiment of the stent 10 having acoating 20 applied thereon in accordance with the present invention.FIG. 3 is likewise an alternative embodiment of the stent 10 having thecoating 20 also applied thereon. The coating 20 is applied to themedical device, such as the stent 10, to provide the stent 10 withdifferent surface properties, and also to provide a vehicle fortherapeutic applications.

In FIG. 2, the coating 20 is applied on both the interior surface 16 andthe exterior surface 18 of the strut 12 forming the stent 10. In otherwords, the coating 20 in FIG. 2 substantially encapsulates the struts 12of the stent 10. In FIG. 3, the coating 20 is applied only on theexterior surface 18 of the stent 10, and not on the interior surface 16of the stent 10. The coating 20 in both configurations is the samecoating; the difference is merely the portion of the stent 10 that iscovered by the coating 20. One of ordinary skill in the art willappreciate that the coating 20 as described throughout the Descriptioncan be applied in both manners shown in FIG. 2 and FIG. 3, in additionto other configurations such as, partially covering select portions ofthe stent 10 structure. All such configurations are described by thecoating 20 reference.

In accordance with embodiments of the present invention, the stent 10includes the coating 20, which is bio-absorbable. The coating 20 has abio-absorbable carrier component, and can also include a therapeuticagent component that can also be bio-absor bable. When applied to amedical device such as a stent 10, it is often desirable for the coatingto inhibit or prevent restenosis. Restenosis is a condition whereby theblood vessel experiences undesirable cellular remodeling after injury.When a stent is implanted in a blood vessel, and expanded, the stentitself may cause some injury to the blood vessel. The treated vesseltypically has a lesion present which can contribute to the inflammationand extent of cellular remodeling. The end result is that the tissue hasan inflammatory response to the conditions. Thus, when a stent isimplanted, there is often a need for the stent to include a coating thatinhibits inflammation, or is non-inflammatory, and prevents restenosis.These coatings have been provided using a number of different approachesas previously described in the Background. However, none of the priorcoatings have utilized a bio-absorbable carrier component to create abio-absorbable coating with suitable non-inflammatory properties forcontrolled release of a therapeutic agent.

In accordance with one embodiment of the present invention, thebio-absorbable carrier component is in the form of a naturally occurringoil. An example of a naturally occurring oil is fish oil or cod liveroil. A characteristic of the naturally occurring oil is that the oilincludes lipids, which contributes to the lipophilic action describedlater herein, that is helpful in the delivery of therapeutic agents tothe cells of the body tissue.

In addition, the naturally occurring oil includes omega-3 fatty acids inaccordance with several embodiments of the present invention. Aspreviously described, omega-3 fatty acids and omega-6 fatty acids areknown as essential fatty acids. Omega-3 fatty acids can be furthercharacterized as eicosapentaenoic acid (EPA), docosahexanoic acid (DHA),and alpha-linolenic acid (ALA). Both EPA and DHA are known to haveanti-inflammatory effects and wound healing effects within the humanbody.

In further detail, the term “bio-absorbable” generally refers to havingthe property or characteristic of being able to penetrate the tissues ofa patient's body. In example embodiments of the present invention, thebio-absorbable coating contains lipids, many of which originate astriglycerides. It has previously been demonstrated that triglycerideproducts such as partially hydrolyzed triglycerides and fatty acidmolecules can integrate into cellular membranes and enhance thesolubility of drugs into the cell. Whole triglycerides are known not toenhance cellular uptake as well as partially hydrolyzed triglyceride,because it is difficult for whole triglycerides to cross cell membranesdue to their relatively larger molecular size. Vitamin E compounds canalso integrate into cellular membranes resulting in decreased membranefluidity and cellular uptake.

It is also known that damaged vessels undergo oxidative stress. Acoating containing an antioxidant such as alpha-tocopherol may aid inpreventing further damage by this mechanism.

Compounds that move too rapidly through a tissue may not be effective inproviding a sufficiently concentrated dose in a region of interest.Conversely, compounds that do not migrate in a tissue may never reachthe region of interest. Cellular uptake enhancers such as fatty acidsand cellular uptake inhibitors such as alpha-tocopherol can be usedalone or in combination to provide an effective transport of a givencompound to a given region or location. Both fatty acids andalpha-tocopherol are accommodated by the coating of the presentinvention described herein. Accordingly, fatty acids andalpha-tocopherol can be combined in differing amounts and ratios tocontribute to a coating in a manner that provides control over thecellular uptake characteristics of the coating and any therapeuticagents mixed therein.

It should further be emphasized that the bio-absorbable nature of thecarrier component and the resulting coating (in the instances where abio-absorbable therapeutic agent component is utilized) results in thecoating 20 being completely absorbed over time by the cells of the bodytissue. There are no substances in the coating, or break down productsof the coating, that induce an inflammatory response. In short, thecoating 20 is generally composed of fatty acids, including in someinstances omega-3 fatty acids, bound to triglycerides, potentially alsoincluding a mixture of free fatty acids and vitamin E. The triglyceridesare broken down by lipases (enzymes) which result in free fatty acidsthat can than be transported across cell membranes. Subsequently, fattyacid metabolism by the cell occurs to metabolize any substancesoriginating with the coating. The bio-absorbable nature of the coatingof the present invention thus results in the coating being absorbed,leaving only an underlying delivery or other medical device structure.There is no foreign body response to the bio-absorbable carriercomponent, including no inflammatory response. The modification of theoils from a more liquid physical state to a more solid, but stillflexible, physical state is implemented through the curing process. Asthe oils are cured, especially in the case of fatty acid-based oils suchas fish oil, cross-links form creating a gel. As the curing process isperformed over increasing time durations and/or increasing temperatureconditions, more cross-links form transitioning the gel from arelatively liquid gel to a relatively solid-like, but still flexible,gel structure.

As previously mentioned, the coating can also include a therapeuticagent component. The therapeutic agent component mixes with thebio-absorbable carrier component as described later herein. Thetherapeutic agent component can take a number of different formsincluding but not limited to anti-oxidants, anti-inflammatory, agents,anti-coagulant agents, drugs to alter lipid metabolism,anti-proliferatives, anti-neoplastics, tissue growth stimulants,functional protein/factor delivery agents, anti-infective agents,anti-imaging agents, anesthetic agents, therapeutic agents, tissueabsorption enhancers, anti-adhesion agents, germicides, antiseptics,proteoglycans, GAG's, gene delivery (polynucleotides), polysaccharides(e.g., heparin), anti-migratory agents, pro-healing agents, ECM/proteinproduction inhibitors, analgesics, prodrugs, and any additional desiredtherapeutic agents such as those listed in Table 1 below.

TABLE #1 CLASS EXAMPLES Antioxidants Alpha-tocopherol, lazaroid,probucol, phenolic antioxidant, resveretrol, AGI-1067, vitamin EAntihypertensive Agents Diltiazem, nifedipine, verapamilAntiinflammatory Agents Glucocorticoids (e.g. dexamethazone,methylprednisolone), leflunomide, NSAIDS, ibuprofen, acetaminophen,hydrocortizone acetate, hydrocortizone sodium phosphate,macrophage-targeted bisphosphonates Growth Factor Angiopeptin, trapidil,suramin Antagonists Antiplatelet Agents Aspirin, dipyridamole,ticlopidine, clopidogrel, GP IIb/IIIa inhibitors, abcximab AnticoagulantAgents Bivalirudin, heparin (low molecular weight and unfractionated),wafarin, hirudin, enoxaparin, citrate Thrombolytic Agents Alteplase,reteplase, streptase, urokinase, TPA, citrate Drugs to Alter LipidFluvastatin, colestipol, lovastatin, atorvastatin, amlopidine Metabolism(e.g. statins) ACE Inhibitors Elanapril, fosinopril, cilazaprilAntihypertensive Agents Prazosin, doxazosin Antiproliferatives andCyclosporine, cochicine, mitomycin C, sirolimus Antineoplasticsmicophenonolic acid, rapamycin, everolimus, tacrolimus, paclitaxel,QP-2, actinomycin, estradiols, dexamethasone, methatrexate, cilostazol,prednisone, cyclosporine, doxorubicin, ranpirnas, troglitzon, valsarten,pemirolast, C- MYC antisense, angiopeptin, vincristine, PCNA ribozyme,2-chloro-deoxyadenosine Tissue growth stimulants Bone morphogeneicprotein, fibroblast growth factor Promotion of hollow Alcohol, surgicalsealant polymers, polyvinyl particles, 2- organ occlusion or octylcyanoacrylate, hydrogels, collagen, liposomes thrombosis FunctionalProtein/Factor Insulin, human growth hormone, estradiols, nitric oxide,delivery endothelial progenitor cell antibodies Second messenger Proteinkinase inhibitors targeting Angiogenic Angiopoetin, VEGF Anti-AngiogenicEndostatin Inhibitation of Protein Halofuginone, prolyl hydroxylaseinhibitors, C-proteinase Synthesis/ECM formation inhibitorsAntiinfective Agents Penicillin, gentamycin, adriamycin, cefazolin,amikacin, ceftazidime, tobramycin, levofloxacin, silver, copper,hydroxyapatite, vancomycin, ciprofloxacin, rifampin, mupirocin, RIP,kanamycin, brominated furonone, algae byproducts, bacitracin, oxacillin,nafcillin, floxacillin, clindamycin, cephradin, neomycin, methicillin,oxytetracycline hydrochloride, Selenium. Gene Delivery Genes for nitricoxide synthase, human growth hormone, antisense oligonucleotides LocalTissue perfusion Alcohol, H2O, saline, fish oils, vegetable oils,liposomes Nitric oxide Donor NCX 4016—nitric oxide donor derivative ofaspirin, Derivatives SNAP Gases Nitric oxide, compound solutions ImagingAgents Halogenated xanthenes, diatrizoate meglumine, diatrizoate sodiumAnesthetic Agents Lidocaine, benzocaine Descaling Agents Nitric acid,acetic acid, hypochlorite Anti-Fibrotic Agents Interferon gamma-1b,Interluekin-10 Immunosuppressive/ Cyclosporine, rapamycin, mycophenolatemotefil, Immunomodulatory Agents leflunomide, tacrolimus, tranilast,interferon gamma-1b, mizoribine Chemotherapeutic Agents Doxorubicin,paclitaxel, tacrolimus, sirolimus, fludarabine, ranpirnase TissueAbsorption Fish oil, squid oil, omega 3 fatty acids, vegetable oils,Enhancers lipophilic and hydrophilic solutions suitable for enhancingmedication tissue absorption, distribution and permeation Anti-AdhesionAgents Hyaluronic acid, human plasma derived surgical sealants, andagents comprised of hyaluronate and carboxymethylcellulose that arecombined with dimethylaminopropyl, ehtylcarbodimide, hydrochloride, PLA,PLGA Ribonucleases Ranpirnase Germicides Betadine, iodine, slivernitrate, furan derivatives, nitrofurazone, benzalkonium chloride,benzoic acid, salicylic acid, hypochlorites, peroxides, thiosulfates,salicylanilide Antiseptics Selenium Analgesics Bupivicaine, naproxen,ibuprofen, acetylsalicylic acid

Some specific examples of therapeutic agents useful in theanti-restenosis realm include cerivastatin, cilostazol, fluvastatin,lovastatin, paclitaxel, pravastatin, rapamycin, a rapamycin carbohydratederivative (for example, as described in US Patent ApplicationPublication 2004/0235762), a rapamycin derivative (for example, asdescribed in U.S. Pat. No. 6,200,985), everolimus, seco-rapamycin,seco-everolimus, and simvastatin. Depending on the type of therapeuticagent component added to the coating, the resulting coating can bebio-absorbable if the therapeutic agent component is alsobio-absorbable. As described in the Summary of the Invention, thepresent invention relates to coating a medical device such as the stent10 with a coating such as coating 20. The coating 20 is formed of atleast two primary components, namely a bio-absorbable carrier componentand a therapeutic agent component. The therapeutic agent component hassome form of therapeutic or biological effect. The bio-absorbablecarrier component can also have a therapeutic or biological effect. Itshould again be noted that the bio-absorbable carrier component isdifferent from the conventional bio-degradable substances utilized forsimilar purposes. The bio-absorbable characteristic of the carriercomponent enables the cells of body tissue of a patient to absorb thebio-absorbable carrier component itself, rather than breaking down thecarrier component into inflammatory by-products and disbursing saidby-products of the component for ultimate elimination by the patient'sbody. Accordingly, anti-inflammatory drug dosages to the patient do notneed to be increased to additionally compensate for inflammation causedby the carrier component, as is otherwise required when usingpolymer-based carriers that themselves cause inflammation.

It should also be noted that the present description makes use of thestent 10 as an example of a medical device that can be coated with thecoating 20 of the present invention. However, the present invention isnot limited to use with the stent 10. Instead, any number of otherimplantable medical devices can be coated in accordance with theteachings of the present invention with the described coating 20. Suchmedical devices include catheters, grafts, balloons, prostheses, stents,other medical device implants, and the like. Implantation refers to bothtemporarily implantable medical devices, as well as permanentlyimplantable medical devices. In the instance of the example stent 10, acommon requirement of stents is that they include some substance oragent that inhibits restenosis. Accordingly, the example coating 20 asdescribed is directed toward the reduction or the elimination ofrestenosis. However, one of ordinary skill in the art will appreciatethat the coating 20 can have other therapeutic or biological benefits.The composition of the coating 20 is simply modified or mixed in adifferent manner to result in a different biological effect.

FIG. 4 illustrates one method of making the present invention, in theform of the coated stent 10, in accordance with one embodiment of thepresent invention. The process involves providing a medical device, suchas the stent 10 (step 100). A coating, such as coating 20, is thenapplied to the medical device (step 102). One of ordinary skill in theart will appreciate that this basic method of application of a coatingto a medical device such as the stent 10 can have a number of differentvariations falling within the process described. Depending on theparticular application, the stent 10 with the coating 20 applied thereoncan be implanted after the coating 20 is applied, or additional stepssuch as curing, sterilization, and removal of solvent can be applied tofurther prepare the stent 10 and coating 20. Furthermore, if the coating20 includes a therapeutic agent that requires some form of activation(such as UV light), such actions can be implemented accordingly.

Furthermore, the step of applying a coating substance to form a coatingon the medical device such as the stent 10 can include a number ofdifferent application methods. For example, the stent 10 can be dippedinto a liquid solution of the coating substance. The coating substancecan be sprayed onto the stent 10, which results in application of thecoating substance on the exterior surface 18 of the stent 10 as shown inFIG. 3. Another alternative application method is painting the coatingsubstance on to the stent 10, which also results in the coatingsubstance forming the coating 20 on the exterior surface 18 as shown inFIG. 3. One of ordinary skill in the art will appreciate that othermethods, such as electrostatic adhesion and other application methods,can be utilized to apply the coating substance to the medical devicesuch as the stent 10. Some application methods may be particular to thecoating substance and/or to the structure of the medical devicereceiving the coating. Accordingly, the present invention is not limitedto the specific embodiment described herein, but is intended to applygenerally to the application of the coating substance to the medicaldevice, taking whatever precautions are necessary to make the resultingcoating maintain desired characteristics.

FIG. 5 is a flowchart illustrating one example implementation of themethod of FIG. 4. In accordance with the steps illustrated in FIG. 5, abio-absorbable carrier component is provided along with a therapeuticagent component (step 110). The provision of the bio-absorbable carriercomponent and the provision of the therapeutic agent component can occurindividually, or in combination, and can occur in any order orsimultaneously. The bio-absorbable carrier component is mixed with thetherapeutic agent component (or vice versa) to form a coating substance(step 112). The coating substance is applied to the medical device, suchas the stent 10, to form the coating (step 114). The coated medicaldevice is then sterilized using any number of different sterilizationprocesses (step 116). For example, sterilization can be implementedutilizing ethylene oxide, gamma radiation, E beam, steam, gas plasma, orvaporized hydrogen peroxide. One of ordinary skill in the art willappreciate that other sterilization processes can also be applied, andthat those listed herein are merely examples of sterilization processesthat result in a sterilization of the coated stent, preferably withouthaving a detrimental effect on the coating 20.

The formation of the bio-absorbable carrier component and thetherapeutic agent component can be done in accordance with differentmethods. FIG. 6 is a flow chart illustrating one example method forforming each of the components. Vitamin E is mixed with a bio-absorbablecarrier to form a bio-absorbable carrier component (step 120). A solventis mixed with a therapeutic agent to form a therapeutic agent component(step 122). The solvent can be chosen from a number of differentalternatives, including ethanol or N-Methyl-2-Pyrrolidone (NMP). Thebio-absorbable carrier component is then mixed with the therapeuticagent component to form the coating substance (step 124). The solventcan then be removed with vacuum or heat. It should be noted that thepreparation of the bio-absorbable carrier component and the therapeuticagent component can be done in either order, or substantiallysimultaneously. Additionally, in an alternative approach, the solventcan be omitted altogether.

In accordance with another embodiment of the present invention a surfacepreparation or pre-treatment 22, as shown in FIG. 8, is provided on astent 10. More specifically and in reference to the flowchart of FIG. 7,a pre-treatment substance is first provided (step 130). Thepre-treatment substance is applied to a medical device, such as thestent 10, to prepare the medical device surface for application of thecoating (step 132). If desired, the pre-treatment 22 is cured (step134). Curing methods can include processes such as application of UVlight or application of heat to cure the pre-treatment 22. A coatingsubstance is then applied on top of the pre-treatment 22 (step 136). Thecoated medical device is then sterilized using any number ofsterilization processes as previously mentioned (step 138).

FIG. 8 illustrates the stent 10 having two coatings, specifically, thepre-treatment 22 and the coating 20. The pre-treatment 22 serves as abase or primer for the coating 20. The coating 20 conforms and adheresbetter to the pre-treatment 22 verses directly to the stent 10,especially if the coating 20 is not heat or UV cured. The pre-treatmentcan be formed of a number of different materials or substances. Inaccordance with one example embodiment of the present invention, thepre-treatment is formed of a bio-absorbable substance, such as anaturally occurring oil (e.g., fish oil). The bio-absorbable nature ofthe pre-treatment 22 results in the pre-treatment 22 ultimately beingabsorbed by the cells of the body tissue after the coating 20 has beenabsorbed.

It has been previously mentioned that curing of substances such as fishoil can reduce or eliminate some of the therapeutic benefits of theomega-3 fatty acids, including anti-inflammatory properties and healingproperties. However, if the coating 20 contains the bio-absorbablecarrier component formed of the oil having the therapeutic benefits, thepre-treatment 22 can be cured to better adhere the pre-treatment 22 tothe stent 10, without losing all of the therapeutic benefits resident inthe pre-treatment 22, or in the subsequently applied coating 20.Furthermore, the cured pre-treatment 22 provides better adhesion for thecoating 20 relative to when the coating 20 is applied directly to thestent 10 surface. In addition, the pre-treatment 22, despite beingcured, remains bio-absorbable. like the coating 20.

The pre-treatment 22 can be applied to both the interior surface 16 andthe exterior surface 18 of the stent 10, if desired, or to one or theother of the interior surface 16 and the exterior surface 18.Furthermore, the pre-treatment 22 can be applied to only portions of thesurfaces 16 and 18, or to the entire surface, if desired.

The application of the coating 20 to the stent 10, or other medicaldevice, can take place in a manufacturing-type facility and subsequentlyshipped and/or stored for later use. Alternatively, the coating 20 canbe applied to the stent 10 just prior to implantation in the patient.The process utilized to prepare the stent 10 will vary according to theparticular embodiment desired. In the case of the coating 20 beingapplied in a manufacturing-type facility, the stent 10 is provided withthe coating 20 and subsequently sterilized in accordance with any of themethods provided herein, and/or any equivalents. The stent 10 is thenpackaged in a sterile environment and shipped or stored for later use.When use of the stent 10 is desired, the stent is removed from thepackaging and implanted in accordance with its specific design.

In the instance of the coating being applied just prior to implantation,the stent can be prepared in advance. The stent 10, for example, can besterilized and packaged in a sterile environment for later use. When useof the stent 10 is desired, the stent 10 is removed from the packaging,and the coating substance is applied to result in the coating 20resident on the stent 10. The coating 20 can result from application ofthe coating substance by, for example, the dipping, spraying, brushing,swabbing, wiping, printing, or painting methods.

The present invention provides the coating 20 for medical devices suchas the stent 10. The coating is bio-absorbable. The coating 20 includesthe bio-absorbable carrier component and can include the therapeuticagent component. The coating 20 of the present invention provides aunique vehicle for the delivery of beneficial substances to the bodytissue of a patient.

The bio-absorbable carrier component itself, in the form of fish oil forexample, can provide therapeutic benefits in the form of reducedinflammation, and improved healing, if the fish oil composition is notsubstantially modified during the process that takes the naturallyoccurring fish oil and forms it into the coating 20. Some prior attemptsto use natural oils as coatings have involved mixing the oil with asolvent, or curing the oil in a manner that destroys the beneficialaspects of the oil. The solvent utilized in the coating 20 of theexemplar embodiment of the present invention (NMP) does not have suchdetrimental effects on the therapeutic properties of the fish oil. Thusthe omega-3 fatty acids, and the EPA and DHA substances aresubstantially preserved in the coating of the present invention.Furthermore, the coating 20 of the present invention is not heat curedor UV light cured to an extent that would destroy all or a substantialamount of the therapeutic benefits of the fish oil, unlike some priorart attempts.

Therefore, the coating 20 of the present invention includes thebio-absorbable carrier component in the form of the naturally occurringoil (i.e., fish oil, or any equivalents). The bio-absorbable carriercomponent is thus able to be absorbed by the cells of the body tissue.More specifically, there is a phospholipid layer in each cell of thebody tissue. The fish oil, and equivalent oils, contain lipids as well.There is a lipophilic action that results where the lipids are attractedby each other in an effort to escape the aqueous environment surroundingthe lipids. Accordingly the lipids attract, the fish oil fatty acidsbind to the cells of the tissue, and subsequently alter cell membranefluidity and cellular uptake. If there is a therapeutic agent componentmixed with the bio-absorbable carrier component, the therapeuticcomponent associated with the fish oil lipids penetrates the cells in analtered manner.

As previously mentioned, prior attempts to create drug deliveryplatforms such as coatings on stents primarily make use of polymer basedcoatings to provide the ability to better control the release of thetherapeutic agent. Essentially, the polymer in the coating releases thedrug or agent at a predetermined rate once implanted at a locationwithin the patient. Regardless of how much of the therapeutic agentwould be most beneficial to the damaged tissue, the polymer releases thetherapeutic agent based on properties of the polymer coating.Accordingly, the effect of the coating is substantially local at thesurface of the tissue making contact with the coating and the stent. Insome instances the effect of the coating is further localized to thespecific locations of stent struts pressed against the tissue locationbeing treated. These prior approaches can create the potential for alocalized toxic effect.

Contrarily with the present invention, because of the lipophilicmechanism enabled by the bio-absorbable lipid based coating 20 formedusing a cross-linked gel derived from at least one fatty acid compoundin accordance with the present invention, the uptake of the therapeuticagent is facilitated by the delivery of the therapeutic agent to thecell membrane by the bio-absorbable carrier component. Further, thetherapeutic agent is not freely released into the body fluids, butrather, is delivered directly to the cells and tissue. In priorconfigurations using polymer based coatings, the drugs were released ata rate regardless of the reaction or need for the drug on the part ofthe cells receiving the drug.

In addition, the bio-absorbable nature of the carrier component and theresulting coating (in the instances where a bio-absorbable therapeuticagent component is utilized) results in the coating 20 being completelyabsorbed over time by the cells of the body tissue. There is no breakdown of the coating into sub parts and substances which induce aninflammatory response that are eventually distributed throughout thebody and in some instances disposed of by the body, as is the case withbiodegradable coatings. The bio-absorbable nature of the coating 20 ofthe present invention results in the coating being absorbed, leavingonly the stent structure, or other medical device structure. There is noforeign body inflammatory response to the bio-absorbable carriercomponent.

Despite action by the cells, the coating 20 of the present invention isfurther configured to release the therapeutic agent component at a rateno faster than a selected controlled release rate over a period of weeksto months. The controlled release rate action is achieved by providingan increased level of vitamin E in the mixture with the fish oil, tocreate a more viscous, sticky, coating substance that better adheres andlasts for a longer duration on the implanted medical device. Thecontrolled release rate can include an initial burst of release,followed by the sustained multi-week to multi-month period of release.Correspondingly, with a greater amount of fatty acids relative to thelevel of vitamin E, the controlled release rate can be increased. Thefatty acids can be found in the oil, and/or fatty acids such as myristicacid can be added to the oil. Thus, the ratio of fatty acids toalpha-tocopherol can be varied in the preparation of the coating 20 tovary the subsequent release rate of the therapeutic agent in acontrolled and predictable manner.

In addition, the oil provides a lubricious surface against the vesselwalls. As the stent 10 having the coating 20 applied thereon isimplanted within a blood vessel, for example, there can be some frictionbetween the stent walls and the vessel walls. This can be injurious tothe vessel walls, and increase injury at the diseased vessel location.The use of the naturally occurring oil, such as fish oil, provides extralubrication to the surface of the stent 10, which reduces the initialinjury. With less injury caused by the stent, there is less of aninflammatory response, and less healing required.

Several example implementations have been carried out to demonstrate theeffectiveness of the coating 20 of the present invention. Detailsconcerning the example implementations follow.

Example #1

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG Fish Oil. Cilostazol was mixed with NMP at a loading of2.5% by weight to form a therapeutic agent component. The bio-absorbablecarrier component was mixed at a ratio of 1:1 with the therapeutic agentcomponent to form a coating substance. The coating substance was appliedto a stent and dried in a vacuum chamber for 15 minutes. The stent withthe coating was then placed in phosphate buffered saline (PBS) fordissolution to measure the delivery of the Cilostazol drug.

Example #2

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% EPAX 3000 TG Fish Oil. Cilostazol was mixed with NMP at a loading of2.5% by weight to form a therapeutic agent component. The bio-absorbablecarrier component was mixed at a ratio of 1:1 with the therapeutic agentcomponent to form a coating substance. The coating substance was appliedto a stent and dried in a vacuum chamber for 15 minutes. The stent withthe coating was then placed in phosphate buffered saline (PBS) fordissolution to measure the delivery of the Cilostazol drug.

Example #3

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% EPAX 3000 TG Fish Oil. Cilostazol was mixed with NMP at a loading of2.5% by weight to form a therapeutic agent component. The bio-absorbablecarrier component was mixed at a ratio of 1:1 with the therapeutic agentcomponent to form a coating substance. The coating substance was appliedto a stent and dried in a vacuum chamber for 15 minutes. The stent wasplaced in an oven for 5 days at 150° F. The stent with the coating wasthen placed in phosphate buffered saline (PBS) for dissolution tomeasure the delivery of the Cilostazol drug.

Example #4

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% EPAX 3000 TG Fish Oil. Cilostazol was mixed with NMP at a loading of2.5% by weight to form a therapeutic agent component. The bio-absorbablecarrier component was mixed at a ratio of 1:1 with the therapeutic agentcomponent to form a coating substance. The coating substance was appliedto a stent and dried in a vacuum chamber for 15 minutes. The stent wasplaced under UV light for 5 days. The stent with the coating was thenplaced in phosphate buffered saline (PBS) for dissolution to measure thedelivery of the Cilostazol drug.

Example #5

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% EPAX 3000 TG Fish Oil. Cilostazol was mixed with NMP at a loading of2.5% by weight to form a therapeutic agent component. The bio-absorbablecarrier component was mixed at a ratio of 1:1 with the therapeutic agentcomponent to form a coating substance. The coating substance was appliedto a stent and dried in a vacuum chamber for 15 minutes. The stent wassent for one cycle of EtO sterilization. The stent with the coating wasthen placed in phosphate buffered saline (PBS) for dissolution tomeasure the delivery of the Cilostazol drug.

Example #6

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% Lorodan Fish Oil Fatty Acids. Cilostazol was mixed with NMP at aloading of 2.5% by weight to form a therapeutic agent component. Thebio-absorbable carrier component was mixed at a ratio of 1:1 with thetherapeutic agent component to form a coating substance. The coatingsubstance was applied to a stent and dried in a vacuum chamber for 15minutes. The stent with the coating was then placed in phosphatebuffered saline (PBS) for dissolution to measure the delivery of theCilostazol drug.

Example #7

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% Lorodan Fish Oil Fatty Acids. Cilostazol was mixed with NMP at aloading of 2.5% by weight to form a therapeutic agent component. Thebio-absorbable carrier component was mixed at a ratio of 1:1 with thetherapeutic agent component to form a coating substance. The coatingsubstance was applied to a stent and dried in a vacuum chamber for 15minutes. The stent was placed in an oven for 5 days at 150° F. The stentwith the coating was then placed in phosphate buffered saline (PBS) fordissolution to measure the delivery of the Cilostazol drug.

Example #8

A bio-absorbable carrier component was made by mixing 15% vitamin E, 35%EPAX 3000 TG Fish Oil, and 50% Myristic Acid. Cilostazol was mixed withNMP at a loading of 2.5% by weight to form a therapeutic agentcomponent. The bio-absorbable carrier component was mixed at a ratio of1:1 with the therapeutic agent component to form a coating substance.The coating substance was applied to a stent and dried in a vacuumchamber for 15 minutes. The stent with the coating was then placed inphosphate buffered saline (PBS) for dissolution to measure the deliveryof the Cilostazol drug.

Example #9

A bio-absorbable carrier component was made by mixing 30% vitamin E,66.5% EPAX 3000 TG Fish Oil, and 3.5% Linseed Oil. Cilostazol was mixedwith NMP at a loading of 2.5% by weight to form a therapeutic agentcomponent. The bio-absorbable carrier component was mixed at a ratio of1:1 with the therapeutic agent component to form a coating substance.The coating substance was applied to a stent and dried in a vacuumchamber for 15 minutes. The stent was placed in an oven for 5 days at150° F. The stent with the coating was then placed in phosphate bufferedsaline (PBS) for dissolution to measure the delivery of the Cilostazoldrug.

The results of the above different example implementations measured overa time period of 5 days showed a range of release rates of theCilostazol drug between about 20 to 65 micrograms at about 1 day toabout 25 to 85 micrograms at about 5 days. In other exampleimplementations using Rapamycin with similar formulations, Rapamycin wasfound present in the vessel tissue after 28 days.

In an additional example implementation, a stent was coated with aprimer or pre-treatment of fish oil prior to the application of the drugloaded coating. The details are provided below.

Example #10

A stainless steel stent was crimped onto a balloon then coated with EPAX3000 TG Fish Oil that was heated at 250° F. for approximately 72 hours.This heating action increased the viscosity of the oil to honey-likeconsistency. The stent was then dipped into a solution of fish oil mixedwith vitamin E and solvent. The stent was placed under vacuum pressureto remove the solvent. Subsequent analysis demonstrated that 10 out of10 sampled areas of the stent maintained a detectable (>μm) amount ofcoating present on the stent, substantially evenly distributed.

Example #11 Control Coating

A bio-absorbable carrier component was made by mixing 50% vitamin E and50% EPAX 3000 TG Fish Oil. The bio-absorbable carrier component wasmixed at a weight ratio of 1:1 with 1-methyl-2-pryrrolidone (NMP) toformulate a coating substance [Formulation A]. The stent/balloon sectionof an Atrium Flyer® coronary stent system was cleaned prior to coatingby dipping it into a sodium bicarbonate solution followed by sonicationin ultrapure HPLC grade water for five minutes. The wet stent/balloonwas removed from the water and dried using flowing hot air for 2minutes. The cleaned stent/balloon was immersion dip coated inFormulation A, then removed and exposed to flowing hot air for 30seconds. The entire stent/catheter assembly was then placed in a vacuumchamber for 15 minutes at a pressure of approximately 50 mTorr. Theassembly was removed from the vacuum chamber, a protector sheath wasplaced over the coated stent/balloon section and the entirestent/catheter assembly was returned to its original hoop packageinsert, then placed in a Tyvek® pouch, sealed and sterilized usingVaporized Hydrogen Peroxide (VHP). After sterilization the packagedassembly was vacuum sealed in a foil pouch.

A representative coated stent was placed in an appropriate dissolutionmedium as a control sample when determining drug release in thefollowing samples.

Example #12 High Dose Rapamycin (˜200 ug/Stent)

A bio-absorbable carrier component was made by mixing 50% vitamin E and50% EPAX 3000 TG Fish Oil. Rapamycin was mixed with1-Methyl-2-Pyrrolidone (NMP) solvent at a loading of 350 mg/ml to form atherapeutic agent component. The bio-absorbable carrier component wasmixed at a weight ratio of 0.5:1 with the therapeutic agent component toformulate a coating substance [Formulation B]. The stent/balloon sectionof an Atrium Flyer® coronary stent system was cleaned prior to coatingby dipping it into a sodium bicarbonate solution followed by sonicationin ultrapure HPLC grade water for five minutes. The wet stent/balloonwas then removed from the water and dried using flowing hot air for 2minutes. The cleaned stent/balloon was then immersion dip coated inFormulation B, then removed and exposed to flowing hot air for 30seconds. The entire stent/catheter assembly was then placed in a vacuumchamber for 15 minutes at a pressure of approximately 50 mTorr. Theassembly was removed from the vacuum chamber, a protector sheath wasplaced over the coated stent/balloon section and the entirestent/catheter assembly was returned to its original hoop packageinsert, then placed in a Tyvek® pouch, sealed and sterilized usingVaporized Hydrogen Peroxide (VHP). After sterilization the packagedassembly was vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 200 ug. A representative coated stent sample was then placed inPhosphate Buffered saline (PBS) for dissolution to measure the rapamycinrelease over time.

Example #13 Low Dose Rapamycin (˜50 ug/Stent)

A bio-absorbable carrier component was made by mixing 50% vitamin F and50% EPAX 3000 TG Fish Oil. Rapamycin was mixed with1-Methyl-2-Pyrrolidone (NMP) solvent at a loading of 85 mg/ml to form atherapeutic agent component. The bio-absorbable carrier component wasmixed at a weight ratio of 0.84:1 with the therapeutic agent componentto formulate a coating substance [Formulation C].

The stent/balloon section of an Atrium Flyer® coronary stent/cathetersystem was cleaned prior to coating by dipping the stent into a sodiumbicarbonate solution followed by sonication in ultrapure 1-IPLC gradewater for five minutes. The wet stent/balloon was removed from the waterand dried using flowing hot air for 2 minutes. The cleaned stent/balloonwas immersion dip coated in Formulation C, and then exposed to flowinghot air for 30 seconds. The entire stent/catheter assembly was thenplaced in a vacuum chamber for 15 minutes at a pressure of approximately50 mTorr. The assembly was removed from the vacuum chamber, and aprotector sheath was placed over the coated stent/balloon section. Theentire stent/catheter assembly was returned to its original hoop packageinsert, then placed in a Tyvek® pouch, sealed and sterilized usingVaporized Hydrogen Peroxide (VHP). After sterilization the packagedassembly was vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 50 ug. A representative coated stent sample was then placed inPhosphate Buffered saline (PBS) for dissolution to measure rapamycinrelease over time.

Example #14 Preparation and Application of Primer

Primer is prepared by heating or UV treating the oil to increase theviscosity. Primer coated stents were prepared for subsequent drugcoating as follows. The stent/balloon section of an Atrium Flyer®coronary stent/catheter system was cleaned prior to primer applicationby dipping into sodium bicarbonate solution followed by sonication inultrapure HPLC grade water for five minutes. The stent/balloon wasremoved from the water and dried using flowing hot air for 2 minutes.EPAX 3000TG fish oil was placed in an oven at 250° F. until theviscosity was of the desired consistency, approximately 30 hours. A thinlayer of the primer was applied evenly around the surface of thepre-crimped stent/balloon, using an applicator. The primer coatedstent/balloon was subsequently coated with the appropriate formulation,as necessary.

Example #15 Hot Cilostazol (˜105 ug/Stent)

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG fish oil. Separately, 100 mg of Cilostazol was mixedwith 0.5 ml of NMP (200 mg/ml concentration). Both the drug-solventmixture and the bio-absorbable carrier component were heated to 150° F.for approximately 10 minutes. Once both mixtures reached temperature,they were combined at a weight ratio of 1:1, gently mixed, and againheated to 150° F. for approximately 5 minutes, until the mixtureequilibrated at 150° F., to formulate a coating substance [FormulationD].

A primer coated Atrium Flyer® stent/balloon was prepared as described inExample #14, and immersion dip coated in Formulation D. The entirestent/catheter assembly was then placed in a vacuum chamber for a periodof 4 hours at a pressure of approximately 50 mTorr. The assembly wasremoved from the vacuum chamber, a protector sheath was placed over thecoated stent/balloon section and the entire stent/catheter assembly wasreturned to its original hoop package insert, then placed in a Tyvek®pouch, sealed and sterilized using Vaporized Hydrogen Peroxide (VHP).After sterilization the packaged assembly was vacuum sealed in a foilpouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 105 ug. A representative coated stent sample was then placed inwater for dissolution to measure release of Cilostazol drug over time.

When viewed under 20× magnification it was evident that there weresubstantially fewer crystals present than there were in a similarformulation that was prepared at room temperature.

Example #16 Cilostazol High Solids (˜388 ug/Stent)

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% EPAX 3000 TG Fish Oil. The bio-absorbable carrier component wasmixed with cilostazol powder at a drug loading of 36% to formulate acoating substance [Formulation E].

The stent/balloon section of an Atrium Flyer® coronary stent system wassonicated in ultrapure HPLC grade water for five minutes. Thestent/balloon was removed from the water and dried using flowing hot airfor 2 minutes. The cleaned stent/balloon was then coated withFormulation E using an applicator. A protector sheath was then placedover the coated stent/balloon section and the entire stent/catheterassembly was returned to its original hoop package insert, placed in aTyvek® pouch, sealed and sterilized using Vaporized Hydrogen Peroxide(VHP). After sterilization the packaged assembly was vacuum sealed in afoil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 388 ug. A representative coated stent sample was then placed inwater for dissolution to measure release of the Cilostazol drug overtime.

Example #17 Methylprednisolone High Solids (˜440 ug/Stent)

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% EPAX 3000 TG Fish Oil. The bio-absorbable carrier component wasmixed with methylprednisolone powder at a drug loading of 40% toformulate a coating substance [Formulation F].

The stent/balloon section of an Atrium Flyer® coronary stent system wascleaned prior to coating by sonication in ultrapure HPLC grade water forfive minutes. The wet stent/balloon was then removed from the water anddried using flowing hot air for 2 minutes. The cleaned stent/balloon wascoated with Formulation F using an applicator. A protector sheath wasthen placed over the coated stent/balloon section and the entirecatheter assembly was returned to its original hoop package insert,placed in a Tyvek® pouch, sealed and sterilized using Vaporized HydrogenPeroxide (VHP). After sterilization the sample was vacuum sealed in afoil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas approximately 550-700 ug. A representative coated stent sample wasthen placed in water for dissolution to measure release of themethylprednisolone drug over time. The amount of methylprednisonereleased over time in water from the coated stent is depicted in FIG. 9.

Example #18 High Dose Methylprednisolone

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% EPAX 3000 TG Fish Oil. Methylprednisolone was mixed with NMP at aloading of 406 mg/ml to form a therapeutic agent component. Thebio-absorbable carrier component was mixed at a weight ratio of 0.37:1with the therapeutic agent component to formulate a coating substance[Formulation G].

The stent/balloon section of an Atrium Flyer® coronary stent system wasprepared and primed as described in Example #14. The primer coatedstent/balloon was then immersion dip coated in Formulation G. The entireassembly was then placed in a vacuum chamber for 4 hours at a pressureof approximately 50 mTorr. The assembly was removed from the vacuumchamber, a protector sheath was placed over the coated stent/balloonsection and the entire assembly was returned to its original hooppackage insert, then placed in a sealed Tyvek® pouch and sterilizedusing Vaporized Hydrogen Peroxide (VHP). After sterilization the samplewas vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 259 ug. A representative coated stent sample was then placed inwater for dissolution to measure the release of the methylprednisolonedrug over time. The amount of methylprednisone released over time inwater from the coated stent is depicted in FIG. 10.

Example #19 Low Dose Cilostazol (˜30 ug/Stent)

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG Fish Oil. Cilostazol was mixed with NMP at a loading of52 mg/ml to form a therapeutic agent component. The bio-absorbablecarrier component was mixed at a weight ratio of 0.9:1 with thetherapeutic agent component to formulate a coating substance[Formulation H].

The stent/balloon section of an Atrium Flyer® coronary stent system wasprepared and primed as described in Example #14. The primer coatedstent/balloon was then immersion dip coated in Formulation H. The entirestent/catheter assembly was then placed in a vacuum chamber for 4 hoursat a pressure of approximately 50 mTorr. The assembly was removed fromthe vacuum chamber, a protector sheath was placed over the coatedstent/balloon section and the entire assembly was returned to itsoriginal hoop package insert, then placed in a Tyvek® pouch, sealed andsterilized using Vaporized Hydrogen Peroxide (VHP). After sterilizationthe sample was vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 30 ug. A representative coated stent sample was then placed in waterfor dissolution to measure the release of the Cilostazol drug over time.The cumulative amount of cilostazol released over time in water from thecoated stent is depicted in FIG. 11.

Example #20 Low Dose Methylprednisolone (30 ug/Stent)

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG Fish Oil. Methylprednisolone was mixed with NMP at aloading of 56 mg/ml to form a therapeutic agent component. Thebio-absorbable carrier component was mixed at a weight ratio of 0.9:1with the therapeutic agent component to formulate a coating substance[Formulation I].

The stent/balloon section of an Atrium Flyer® coronary stent system wasprepared and primed as described in Example #14. The primer coatedstent/balloon was then immersion dip coated in Formulation I. The entirestent/catheter assembly was then placed in a vacuum chamber for 4 hoursat a pressure of approximately 50 mTorr. The assembly was removed fromthe vacuum chamber, a protector sheath was placed over the coatedstent/balloon section and the entire assembly was returned to itsoriginal hoop package insert, then placed in a Tyvek® pouch, sealed andsterilized using Vaporized Hydrogen Peroxide (VHP). After sterilizationthe sample was vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 30 ug. A representative coated stent sample was then placed in waterfor dissolution to measure release of the methylprednisolone drug overtime.

Example #21 Paclitaxel High Solids (106 ug/Stent)

A bio-absorbable carrier component was made by mixing 30% vitamin E and70% EPAX 3000 TG Fish Oil. The bio-absorbable carrier component wasmixed with paclitaxel powder at a drug loading of 11% to formulate acoating substance [Formulation J].

The stent/balloon section of an Atrium Flyer® coronary stent system wascleaned prior to coating by sonication in ultrapure HPLC grade water forfive minutes. The wet stent/balloon was then removed from the water anddried using flowing hot air for 2 minutes. The cleaned stent/balloon wasthen coated with Formulation J using an applicator. A protector sheathwas then placed over the coated stent/balloon section and the entireassembly was returned to its original hoop package insert, placed in asealed Tyvek® pouch and sterilized using Vaporized Hydrogen Peroxide(VHP). After sterilization the sample was vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 106 ug. A representative coated stent sample was then placed in 35%Acetonitrile/water for dissolution to measure release of the paclitaxeldrug over time. The amount of paclitaxel released over time in a 35%solution of acetonitrile/water from the coated stent is depicted in FIG.12.

Example #22 Medium Dose Paclitaxel (30 ug/Stent)

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG Fish Oil. Paclitaxel was mixed with Ethanol at aloading of 40 mg/ml to form a therapeutic agent component. Thebio-absorbable carrier component was mixed at a weight ratio of 0.94:1with the therapeutic agent component to formulate a coating substance[Formulation K].

The stent/balloon section of an Atrium Flyer® coronary stent system wasprepared and primed as described in Example #14. The primer coatedstent/balloon was then immersion dip coated in Formulation K. The entireassembly was then placed in a vacuum chamber for 4 hours at a pressureof approximately 50 mTorr. The assembly was removed from the vacuumchamber, a protector sheath was placed over the coated stent/balloonsection and the entire assembly was returned to its original hooppackage insert, then placed in a sealed Tyvek® pouch and sterilizedusing Vaporized Hydrogen Peroxide (VHP). After sterilization the samplewas vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 30 ug. A representative coated stent sample was then placed in 35%Acetonitrile/water for dissolution to measure release of the paclitaxeldrug over time.

Example #23 Low Dose Paclitaxel (5 ug/Stent)

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG Fish Oil. Paclitaxel was mixed with Ethanol at aloading of 8 mg/ml to form a therapeutic agent component. Thebio-absorbable carrier component was mixed at a weight ratio of 1:1 withthe therapeutic agent component to formulate a coating substance[Formulation L].

The stent/balloon section of an Atrium Flyer® coronary stent system wasprepared and primed as described in Example #14. The primer coatedstent/balloon was then immersion dip coated in Formulation L. The entireassembly was then placed in a vacuum chamber for 4 hours at a pressureof approximately 50 mTorr. The assembly was removed from the vacuumchamber, a protector sheath was placed over the coated stent/balloonsection and the entire assembly was returned to its original hooppackage insert, then placed in a sealed Tyvek® pouch and sterilizedusing Vaporized Hydrogen Peroxide (VHP). After sterilization the samplewas vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 5 ug. A representative coated stent sample was then placed in 35%Acetonitrile/water for dissolution to measure release of the paclitaxeldrug over time.

Example #24 High Dose Rapamycin (˜200 ug/Stent)

A bio-absorbable carrier component was made by mixing 50% vitamin E and50% EPAX 3000 TG Fish Oil. Rapamycin was mixed with NMP at a loading of350 mg/ml to form a therapeutic agent component. The bio-absorbablecarrier component was mixed at a weight ratio of 0.5:1 with thetherapeutic agent component to formulate a coating substance[Formulation M].

The stent/balloon section of an Atrium Flyer® coronary stent system wascleaned prior to coating by sonication in ultrapure HPLC grade water forfive minutes. The wet stent/balloon was then removed from the water anddried using a flowing hot air for 2 minutes. The cleaned stent/balloonwas then immersion dip coated in Formulation M then exposed to flowinghot air. The entire assembly was then placed in a vacuum chamber for 4hours at a pressure of approximately 50 mTorr. The assembly was removedfrom the vacuum chamber, a protector sleeve was placed over thestent/balloon section and the entire assembly was returned to itsoriginal hoop package insert, then placed in a Tyvek® pouch, sealed andsterilized using Vaporized Hydrogen Peroxide (VHP). After sterilizationthe sample was vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 200 ug. A representative coated stent sample was then placed inPhosphate Buffered saline (PBS) for dissolution to measure release ofthe rapamycin drug over time.

Example #25 Pre-Dried Paclitaxel Formulation

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG Fish Oil, as prepared in Example #14. Paclitaxel wasmixed with Ethanol at a loading of 39 mg/ml to form a therapeutic agentcomponent. The bio-absorbable carrier component was mixed at a weightratio of 0.9:1 with the therapeutic agent component to formulate acoating mixture. The coating mixture was then placed in a vacuum chamberat a pressure of approximately 50 mTorr for a period of 16 hours toformulate a coating substance [Formulation N].

The coating substance was highly viscous and free from crystalformation. The stent/balloon section of an Atrium Flyer® coronary stentsystem was then cleaned prior to coating by sonication in ultrapure HPLCgrade water for five minutes. The wet stent/balloon section was thenremoved from the water and dried using a flowing hot air for 2 minutes.The cleaned stent/balloon was then coated with the Formulation N usingan applicator. A protector sheath was then placed over the coatedstent/balloon section and the entire assembly was returned to itsoriginal hoop package insert, placed in a sealed Tyvek® pouch andsterilized using Vaporized Hydrogen Peroxide (VHP). After sterilizationthe sample was vacuum sealed in a foil pouch.

The calculated amount of drug on a 3.0×16 mm stent with this formulationwas 50 ug. A representative coated stent sample was then placed in 35%acetonitrile/water for dissolution to measure release of the Paclitaxeldrug over time.

Example #26 Pre Dried Cilostazol Formulation

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG Fish Oil, as prepared in Example #14. Cilostazol wasmixed with NMP at a loading of 24 mg/ml to form a therapeutic agentcomponent. The bio-absorable carrier component was mixed at a weightratio of 0.86:1 with the therapeutic agent component to form a coatingmixture. The coating mixture was then placed in a vacuum chamber at apressure of approximately 50 mTorr for a period of 16 hours to formulatea coating substance [Formulation O].

A highly viscous coating substance that was free of crystals wasobtained. The stent/balloon section of an Atrium Flyer® coronary stentsystem was then cleaned prior to coating by sonication in ultrapure HPLCgrade water for five minutes. The wet stent/balloon section was thenremoved from the water and dried using flowing hot air for 2 minutes.The cleaned stent/balloon was then coated with Formulation O using anapplicator. A protector sheath was then placed over the coatedstent/balloon section and the entire assembly was returned to itsoriginal hoop package insert, placed in a sealed Tyvek® pouch andsterilized using Vaporized Hydrogen Peroxide (VHP). After sterilizationthe sample was vacuum sealed in a foil pouch.

A representative coated stent sample was then placed in phosphatebuffered saline solution (PBS) for dissolution to measure release of theCilostazol drug over time.

Example #27 Pre Dried Rapamycin Formulation

A bio-absorbable carrier component was made by mixing 70% vitamin E and30% EPAX 3000 TG Fish Oil. Rapamycin was mixed with NMP at a loading of97 mg/ml to form a therapeutic agent component. The bio-absorbablecarrier component was mixed at a weight ratio of 0.77:1 with thetherapeutic agent component to form a coating mixture. The coatingmixture was then placed in a vacuum chamber at a pressure ofapproximately 50 mTorr for a period of 16 hours to formulate a coatingsubstance [Formulation P].

The coating mixture was highly viscous and free from crystal formation.The stent/balloon section of an Atrium Flyer® coronary stent system wasthen cleaned prior to coating by sonication in ultrapure HPLC gradewater for five minutes. The wet stent/balloon section was then removedfrom the water and dried using flowing hot air for 2 minutes. Thecleaned stent/balloon was then coated with the Formulation P using anapplicator. A protector sheath was then placed over the coatedstent/balloon section and the entire assembly was returned to itsoriginal hoop package insert, placed in a sealed Tyvek® pouch andsterilized using Vaporized Hydrogen Peroxide (VHP). After sterilizationthe sample was vacuum sealed in a foil pouch.

A representative coated stent sample was then placed in phosphatebuffered saline solution (PBS) for dissolution to measure release of theRapamycin drug over time.

Example #28 Animal Study

Several different stent and coating combinations were created andimplanted into rabbit iliac arteries for 28 days and then histopathology(a measure of biological response to an implant at the cellular level)and histomorphometry (a measure of the neoinitimal thickness and lumenarea of the stented vessel) were performed. A bare stent (stent A), astent having a non-polymer coating of the present invention (stent B),and a stent having a non-polymer coating including a drug (Rapamycin)(stent C) were the three stent and coating combinations using an AtriumMedical Corporation Flyer™ stainless steel stent that were implanted. Apolymer coated stent with drug (Rapamycin) made by Johnson & Johnson(Cypher™ stent) (stent D) was a fourth stent combination implanted.

Example #29 Release Rate Comparison

Three coatings in accordance with the present invention were applied tothe stents having coatings, and the release rates compared. The resultsare shown in FIG. 13.

Referring to FIG. 13, the top diamond line on the curve that is labeled“[high dose]” is a 30.1% Rapamycin formulation made with 50% vitamin Eand 50% fish oil. The drug was dissolved in the solvent (NMP) first andthen combined with the fish oil/vitamin E mixture and vortexed. Thesolvent was then removed with vacuum. The formulation was dip coated onstents and then dried over night in a bell jar. The stent was thenexpanded and submitted for release testing.

The next line on the graph that is labeled “[low dose]” is a samplecontaining 18.49% rapamycin in a coating that is 30% Vitamin E and 70%fish oil. The coating was made using NMP as the solvent. The solvent wasthen removed with vacuum. The stent was then expanded and submitted forrelease testing.

The next line on the graph that is labeled “Cypher stent” was a Cypherstent, measuring 2.5×18 mm. Drug release was measured from an expandedstent.

The final line on the graph that is labeled “[high dose]XR” was a 19.18%Rapamycin insoluble formulation that was made in 30% vitamin E and 70%thickened fish oil. This sample had no solvent and was applied using astent protector. The sample was then expanded and submitted for releasetesting.

For purposes of the analysis, the Stents are put into 4 ml vials alongwith 4 ml of PBS on the incubated (37° C.) shaker table and samples aretaken at appropriate time points for measuring drugconcentration/release using HPLC. When the stent was ready to be sampledthe stent was removed from the vial and put in a new vial with a fresh 4mls of PBS and returned to the incubated shaker. The sample was preparedfor HPLC by adding 600 ul of the PBS from the test sample to 3400 ul ofMethanol to obtain an 85:15 ratio. The sample was then mixed using thevortexer. This methanol diluted sample was then injected onto the HPLCand drug release was calculated.

The stents loaded with the bio-absorbable coating of the presentinvention and low (50 μg) amounts of Rapamycin (labeled [low dose]stent) and the stents loaded with the bio-absorbable coating of thepresent invention and high (200 ug) amounts of Rapamycin (labeled [highdose] stent) implanted in the iliac arteries were well tolerated andproduced no adverse reactions.

The stents having the bio-absorbable coating of the present inventionand loaded with Rapamycin significantly reduced neointimal growth, andexperienced delayed healing, but the stents were well endothelializedafter 28 days. The stents having the bio-absorbable coating of thepresent invention and the stents having the bio-absorbable coating ofthe present invention with drug caused relatively less arterial injuryrelative to the Cypher™ stent (labeled “Cypher stent”), which causedmore than twice the amount of arterial injury. The Cypher™ stentproduced the greatest reduction in neointimal growth, however also hadthe greatest delay in healing, which was represented by fibrindeposition and poor endothelialization relative to the other implantedstents. The Cypher™ stent also experience relatively greater numbers ofinflammatory and giant cells relative to the other implanted stents. TheCypher™ stents experienced at least three times greater amounts of giantcell reaction and the majority of Cypher™ stent struts showed presenceof eosinophils, which were rarely present on the other implanted stents.

Numerous modifications and alternative embodiments of the presentinvention will be apparent to those skilled in the art in view of theforegoing description. Accordingly, this description is to be construedas illustrative only and is for the purpose of teaching those skilled inthe art the best mode for carrying out the present invention. Details ofthe structure may vary substantially without departing from the spiritof the invention, and exclusive use of all modifications that comewithin the scope of the appended claims is reserved. It is intended thatthe present invention be limited only to the extent required by theappended claims and the applicable rules of law.

What is claimed is:
 1. A coated medical device, comprising: the medicaldevice; and a coating disposed on the medical device, the coatingcomprising: a bio-absorbable cross-linked material; a cellular uptakeinhibitor; and a therapeutic agent; wherein the bio-absorbablecross-linked material comprises two or more omega-3 fatty acidscross-linked into a substantially random configuration by ester bonds.2. The device of claim 1, wherein the cellular uptake inhibitorcomprises alpha-tocopherol.
 3. The device of claim 1, wherein the two ormore omega-3 fatty acids comprise eicosapentaenoic acid (EPA).
 4. Thedevice of claim 1, wherein the two or more omega-3 fatty acids comprisedocosahexaenoic acid (DHA).
 5. The device of claim 1, wherein the two ormore omega-3 fatty acids comprise α-linolenic acid (ALA).
 6. The deviceof claim 1, wherein the bio-absorbable cross-linked material is derivedfrom a naturally occurring oil, an oil composition, or both.
 7. Thedevice of claim 1, wherein the bio-absorbable cross-linked material isderived from fish oil.
 8. The device of claim 1, wherein the therapeuticagent comprises one or more agents selected from the group of agentsconsisting of antioxidants, anti-inflammatory agents, anti-coagulantagents, drugs to alter lipid metabolism, anti-proliferatives,anti-neoplastics, anti-fibrotics, immunosuppressive, tissue growthstimulants, functional protein/factor delivery agents, anti-infectiveagents, imaging agents, anesthetic agents, chemotherapeutic agents,tissue absorption enhancers, anti-adhesion agents, germicides,antiseptics, proteoglycans, GAG's, polynucleotides, analgesics,prodrugs, or polysaccharides.
 9. The device of claim 1, wherein thetherapeutic agent component comprises one or more agents selected fromthe group of agents consisting of cerivastatin, cilostazol, fluvastatin,lovastatin, paclitaxel, pravastatin, rapamycin, or simvastatin.
 10. Thedevice of claim 1, wherein the medical device comprises a stent.
 11. Thedevice of claim 10, wherein the stent is formed of one or more substanceselected from the group of substances consisting of stainless steel,Nitinol alloy, nickel alloy, titanium alloy, cobalt-chromium alloy,ceramics, metals, plastics, or polymers.
 12. The device of claim 1,further comprising a pre-treatment provided between the medical deviceand the coating comprising omega-3 fatty acids, wherein thepre-treatment improves consistency and conformability and enhances theadhesion of the coating comprising the bio-absorbable carrier component.13. The device of claim 12, wherein the pre-treatment is bio-absorbable.14. The device of claim 12, wherein the pre-treatment comprises anaturally occurring oil, an oil composition, or both.
 15. The device ofclaim 12, wherein the pre-treatment comprises fish oil.
 16. The deviceof claim 12, wherein the pre-treatment is modified from its naturallyoccurring state to a state of increased viscosity in the form of across-linked material.
 17. The device of claim 16, wherein themodification of the pre-treatment from its naturally occurring state tothe state of increased viscosity occurs prior to application of thepre-treatment on the device.
 18. A method of making a coated medicaldevice, the method comprising: providing the medical device; and coatingthe medical device with a bio-absorbable cross-linked material, acellular uptake inhibitor, and a therapeutic agent; wherein thebio-absorbable cross-linked material comprises two or more omega-3 fattyacids cross-linked into a substantially random configuration by esterbonds.
 19. The method of claim 18, wherein the cellular uptake inhibitorcomprises alpha-tocopherol.
 20. The method of claim 18, wherein thebio-absorbable cross-linked material comprises a naturally occurringoil, an oil composition, or a combination of both, that have undergoneat least partial curing in an amount sufficient to form thesubstantially random configuration of cross-linked ester bonds.
 21. Themethod of claim 18, wherein the omega-3 fatty acids are supplied fromfish oil.
 22. The method of claim 18, wherein bonds of the substantiallyrandom configuration of ester bonds forming the cross-linked fatty acidsare formed prior to the step of coating the medical device.
 23. Themethod of claim 18, wherein the step of coating comprises applyingomega-3 fatty acids to the medical device and curing the omega-3 fattyacids to form substantially random configuration of ester bonds formingthe cross-linked fatty acids.
 24. The method of claim 18, wherein thetherapeutic agent component comprises one or more agents selected fromthe group of agents consisting of antioxidants, anti-inflammatoryagents, anti-coagulant agents, drugs to alter lipid metabolism,anti-proliferatives, anti-neoplastics, anti-fibrotics,immunosuppressives, tissue growth stimulants, functional protein/factordelivery agents, anti-infective agents, imaging agents, anestheticagents, chemotherapeutic agents, tissue absorption enhancers,anti-adhesion agents, germicides, antiseptics, proteoglycans, GAG's,polynucleotides, analgesics, prodrugs, or polysaccharides (heparin). 25.The method of claim 18, wherein the therapeutic agent componentcomprises one or more agents selected from the group of agentsconsisting of cerivastatin, cilostazol, fluvastatin, lovastatin,paclitaxel, pravastatin, rapamycin, or simvastatin.
 26. The method ofclaim 18, wherein the omega-3 fatty acids comprise eicosapentaenoic acid(EPA) and docosahexanoic acid (DHA).
 27. The method of claim 18, whereinthe medical device comprises a stent.
 28. The method of claim 27,wherein the stent is formed of one or more substances selected from thegroup of substances consisting of stainless steel, Nitinol alloy, nickelalloy, titanium alloy, cobalt-chromium alloy, ceramics, metals,plastics, or polymers.
 29. The method of claim 18, further comprisingproviding a pre-treatment between the medical device and the coatingcomprising omega-3 fatty acids, wherein the pre-treatment improvesconsistency and conformability and enhances the adhesion of the coatingcomprising the bio-absorbable carrier component.
 30. The method of claim29, wherein the pre-treatment is bio-absorbable.
 31. The method of claim29, wherein the pre-treatment comprises a naturally occurring oil, anoil composition, or both.
 32. The method of claim 29, wherein thepre-treatment comprises fish oil.
 33. The method of claim 29, furthercomprising modifying the pre-treatment from its naturally occurringstate to a state of increased viscosity in the form of a cross-linkedmaterial.
 34. The method of claim 18, further comprising forming thebio-absorbable cross-linked material by curing while on the medicaldevice.
 35. The method of claim 34, wherein curing comprises applying atleast one curing method selected from a group of curing methodscomprised of heat or UV light.
 36. A coated medical device, comprising:a pre-treatment provided on the medical device having a firstbio-absorbable cross-linked material; and a coating disposed on top ofthe pre-treatment, the coating having a second bio-absorbablecross-linked material, a cellular uptake inhibitor, a therapeutic agent;wherein the pre-treatment improves consistency and conformability andenhances the adhesion of the coating to the medical device; wherein thecoated medical device is implantable in a patient to effect controlleddelivery of the therapeutic agent to the patient; wherein the controlleddelivery is at least partially characterized by total and relativeamounts of the cellular uptake inhibitor and bio-absorbable cross-linkedmaterial; and wherein the bio-absorbable cross-linked material comprisestwo or more omega-3 fatty acids cross-linked into a substantially randomconfiguration by ester bonds.
 37. The device of claim 36, wherein thecellular uptake inhibitor comprises alpha-tocopherol.
 38. The device ofclaim 36, wherein the omega-3 fatty acids comprise eicosapentaenoic acid(EPA) and docosahexanoic acid (DHA).
 39. The device of claim 36, whereinthe medical device comprises a stent.